Genetic diseases - Direct result of a mutation in one gene = monogenetic trait
e.g. albino mutation
- Due to a combination of mutated alleles: usually not due to
loss-of-function alleles
Pedigree analysis The pattern of inheritance of monogenic disorders can deduced by
analysing human pedigrees.
Modes of inheritance
Autosomal recessive inheritance
1. Frequently, an affected offspring will have two
unaffected parents
2. When two unaffected heterozygotes have children,
the percentage of affected children is (on average)
25%
3. Two affected individuals will have 100% affected
children -> only when a recessive trait produces
fertile, viable individuals.
4. The trait occurs with the same frequency in both
sexes
5. Skip generations
Disorders that involve defective enzyme typically have an autosomal
recessive mode of inheritance. The heterozygote has 50% of the
normal enzyme. This is often insufficient for an normal phenotype, but
not always: incomplete dominance/ haplo-insufficiency
Autosomal dominant inheritance
1. An affected offspring usually has one or both affected
parents, but not always sometimes incomplete penetrance.
- Usually affected individuals in every generation. It simply
occurs more often because one dominant allele is sufficient.
- If this is not the case, it is likely a new germline mutation (so
affected offspring can have two unaffected parents).
2. An affected individual (with one affected parent) produces
50% affected offspring, on average.
Mutated gene encodes a protein named 3. Two affected parents produce 75% affected offspring, on
huntingtin average.
- The mutation adds a polyglutamine tract 4. The trait occurs with the same frequency in both sexes
to the protein
- Triplet repeat expansion
- This causes aggregation of the protein in
neurons
>> a gain of function mutation > dominant
behavior
>> one copy of the dominant allele
sufficient t!
, Three common explanations for dominant disorders
Haplo-insufficience/ incomplete dominance Loss of function mutation/allele.
- Half amount of protein is produced, so The heterozygote has 50% of the normal protein ( a single functional
normal production is not working. copy of a gene), this is not sufficient for a normal phenotype.
Haplo-insufficiency shows a dominant pattern of inheritance because a
heterozygote (one functional allele and one inactive allele) has the
disease.
Gain of function mutation Mutation changes protein so it gained a new or abnormal function.
- Normal production still goes on but E.g. mutant allele is overly active and disrupts a signalling pathway.
affected but mutated allele.
Dominant negative mutation The altered gene product acts antagonistically to the normal product.
- Normal production still goes on but Mutant allele opposes the effects of the normal protein.
affected by mutated allele.
Models of inheritance
X-linked recessive inheritance
This type of inheritance poses a special
problems for males. Males have only a single
copy of most X-linked genes = hemizygous. A
female carrier will pas this trait to half of her
sons.
1. Males are much more likely
to exhibit the trait
2. The mothers of affected males often have brothers or
fathers who are affected with the same trait
3. The daughters of affected males will produce (on
average) 50% affected sons.
X-linked dominant inheritance -> rare
Most cases males are more severly affected than females, because
females carry also an X-chromsome with a normal copy of the gene.
Often Males die at early age, so mostly female exhibit the disease.
Most of the time these disoreders are caused by new mutations that
occur during gamete formation or early embryogenesis.
1. Only females exhibit the trait when it is lethal to males
2. Affected mother have a 50% chance of passing the trait to
daughters.
Locus heterogeneity The phenomenon that a disease is caused by mutations in different
genes. E.g. hemophilia.
Locus heterogeneity may grealty confound pedigree analysis.
Examples of diseases with complex pattern of inhertiance (involve
mutiple genes); diabetes, asthma, mental illness, cancer.
e.g. albino mutation
- Due to a combination of mutated alleles: usually not due to
loss-of-function alleles
Pedigree analysis The pattern of inheritance of monogenic disorders can deduced by
analysing human pedigrees.
Modes of inheritance
Autosomal recessive inheritance
1. Frequently, an affected offspring will have two
unaffected parents
2. When two unaffected heterozygotes have children,
the percentage of affected children is (on average)
25%
3. Two affected individuals will have 100% affected
children -> only when a recessive trait produces
fertile, viable individuals.
4. The trait occurs with the same frequency in both
sexes
5. Skip generations
Disorders that involve defective enzyme typically have an autosomal
recessive mode of inheritance. The heterozygote has 50% of the
normal enzyme. This is often insufficient for an normal phenotype, but
not always: incomplete dominance/ haplo-insufficiency
Autosomal dominant inheritance
1. An affected offspring usually has one or both affected
parents, but not always sometimes incomplete penetrance.
- Usually affected individuals in every generation. It simply
occurs more often because one dominant allele is sufficient.
- If this is not the case, it is likely a new germline mutation (so
affected offspring can have two unaffected parents).
2. An affected individual (with one affected parent) produces
50% affected offspring, on average.
Mutated gene encodes a protein named 3. Two affected parents produce 75% affected offspring, on
huntingtin average.
- The mutation adds a polyglutamine tract 4. The trait occurs with the same frequency in both sexes
to the protein
- Triplet repeat expansion
- This causes aggregation of the protein in
neurons
>> a gain of function mutation > dominant
behavior
>> one copy of the dominant allele
sufficient t!
, Three common explanations for dominant disorders
Haplo-insufficience/ incomplete dominance Loss of function mutation/allele.
- Half amount of protein is produced, so The heterozygote has 50% of the normal protein ( a single functional
normal production is not working. copy of a gene), this is not sufficient for a normal phenotype.
Haplo-insufficiency shows a dominant pattern of inheritance because a
heterozygote (one functional allele and one inactive allele) has the
disease.
Gain of function mutation Mutation changes protein so it gained a new or abnormal function.
- Normal production still goes on but E.g. mutant allele is overly active and disrupts a signalling pathway.
affected but mutated allele.
Dominant negative mutation The altered gene product acts antagonistically to the normal product.
- Normal production still goes on but Mutant allele opposes the effects of the normal protein.
affected by mutated allele.
Models of inheritance
X-linked recessive inheritance
This type of inheritance poses a special
problems for males. Males have only a single
copy of most X-linked genes = hemizygous. A
female carrier will pas this trait to half of her
sons.
1. Males are much more likely
to exhibit the trait
2. The mothers of affected males often have brothers or
fathers who are affected with the same trait
3. The daughters of affected males will produce (on
average) 50% affected sons.
X-linked dominant inheritance -> rare
Most cases males are more severly affected than females, because
females carry also an X-chromsome with a normal copy of the gene.
Often Males die at early age, so mostly female exhibit the disease.
Most of the time these disoreders are caused by new mutations that
occur during gamete formation or early embryogenesis.
1. Only females exhibit the trait when it is lethal to males
2. Affected mother have a 50% chance of passing the trait to
daughters.
Locus heterogeneity The phenomenon that a disease is caused by mutations in different
genes. E.g. hemophilia.
Locus heterogeneity may grealty confound pedigree analysis.
Examples of diseases with complex pattern of inhertiance (involve
mutiple genes); diabetes, asthma, mental illness, cancer.
